title: Bortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2A.
abstract: Previously, we have shown that bortezomib overcame TRAIL resistance in hepatocellular carcinoma (HCC) cells via the inhibition of Akt. Here, we report that bortezomib sensitizes these TRAIL-resistant cells, including Huh-7, Hep3B, and Sk-Hep1, to CS-1008, a humanized agonistic antihuman death receptor 5 antibody. Cancerous inhibitor of protein phosphatase 2A (CIP2A) mediated the sensitizing effect of bortezomib to CS-1008 through inhibiting protein phosphatase 2A (PP2A) activity. Combination treatment of bortezomib and CS-1008 downregulated CIP2A in a concentration- and time-dependent manner, and increased PP2A activity in HCC cells. Importantly, ectopic expression of CIP2A decreased Akt-related PP2A activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells. Moreover, silencing CIP2A by short interfering RNA enhanced CS-1008-induced apoptosis in HCC cells and ectopic expression of CIP2A in HCC cells abolished CS-1008-induced apoptosis, indicating that CIP2A plays an important role in the sensitizing effect of bortezomib to CS-1008. Finally, our in vivo data showed that CS-1008 and bortezomib combination treatment decreased tumor growth significantly. In conclusion, bortezomib sensitized HCC cells to CS-1008 through the inhibition of CIP2A.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Chen
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Chen
authors.forename: Duen-Ren
authors.initials: DR
authors.lastname: Hou
authors.forename: Pei-Jer
authors.initials: PJ
authors.lastname: Chen
authors.forename: Ann-Lii
authors.initials: AL
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000912:Antibodies, Neoplasm / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001324:Autoantigens / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008113:Liver Neoplasms / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000912:Antibodies, Neoplasm; D001324:Autoantigens; D001897:Boronic Acids; C500266:CIP2A protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011719:Pyrazines; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000069286:Bortezomib; D051057:Proto-Oncogene Proteins c-akt; D054648:Protein Phosphatase 2